Endoprosthesis with coatings

ABSTRACT

An endoprosthesis such as a coronary stent includes a polymeric reservoir of drug and an over coating formed of ceramic or metal for controlling elution of drag from the reservoir.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Provisional PatentApplication No. 60/857,849, filed Nov. 9, 2006, the entire contents ofwhich is hereby incorporated by reference.

TECHNICAL FIELD

This invention relates to endoprostheses with coatings.

BACKGROUND

The body includes various passageways such as arteries, other bloodvessels, and other body lumens. These passageways sometimes becomeoccluded or weakened. For example, the passageways can be occluded by atumor, restricted by plaque, or weakened by an aneurysm. When thisoccurs, the passageway can be reopened or reinforced with a medicalendoprosthesis. An endoprosthesis is typically a tubular member that isplaced in a lumen in the body. Examples of endoprostheses includestents, covered stents, and stent-grafts.

Endoprostheses can be delivered inside the body by a catheter thatsupports the endoprosthesis in a compacted or reduced-size form as theendoprosthesis is transported to a desired site. Upon reaching the site,the endoprosthesis is expanded, e.g., so that it can contact the wallsof the lumen. Stent delivery is further discussed in Heath, U.S. Pat.No. 6,290,721, the entire contents of which is hereby incorporated byreference herein.

The expansion mechanism may include forcing the endoprosthesis to expandradially. For example, the expansion mechanism can include the cathetercarrying a balloon, which carries a balloon-expandable endoprosthesis.The balloon can be inflated to deform and to fix the expandedendoprosthesis at a predetermined position in contact with the lumenwall. The balloon can then be deflated, and the catheter withdrawn fromthe lumen.

Passageways containing endoprostheses can become re-occluded.Re-occlusion of such passageways is known as restenosis. It has beenobserved that certain drugs can inhibit the onset of restenosis when thedrug is contained in the endoprosthesis. It is sometimes desirable foran endoprosthesis-contained therapeutic agent, or drug to elute into thebody fluid in a predetermined manner once the endoprosthesis isimplanted.

SUMMARY

In an aspect, the document features an endoprosthesis having a firstcoating including a polymer, and a second coating over the first coatingformed of a porous ceramic or metal.

In another aspect, the document features a method of forming anendoprosthesis, including forming a polymer coating that has a drug onthe endoprosthesis, and forming a layer of porous ceramic or metal overthe drug-containing polymer coating.

Embodiments may include one or more of the following features. Thepolymer can include a drug. The polymer can have a drug content of about8.8% by weight or more (e.g., 15% or more, 25% or more). The polymer canbe a non-biodegradable polymer such as styrene-isobutylene-styrene(SIBS) or polybutylene succinate (PBS). The first coating can have aplurality of depressions. The second coating can be formed of a porousceramic. The second coating can have pores with a pore diameter of about1 nm to 20 nm. The ceramic can be an oxide. The ceramic can be iridiumoxide (IROX), titanium oxide (TIOX), tantalum oxide, or niobium oxide.The ceramic can have a smooth globular morphology to enhance endothelialcell growing over the ceramic. The ceramic can have a porosity of about80% or less. The second coating can have a thickness less than thethickness of the first coating. The thickness of the second coating canbe about 10 to 500 nm. The thickness of the first coating is about 0.1to about 10 micron (e.g., about 0.5 to about 3 micron). The firstcoating can contact a surface of an endoprosthesis body. Theendoprosthesis body can be formed of a metal. The metal is stainlesssteel. The endoprosthesis body can be formed of a polymer. The polymercan be a biostable polymer. The polymer can be a bioerodible polymer.The second coating can be formed of porous metal. The porous metal canbe copper, gold, ruthenium, titanium, tantalum, platinum, palladium,stainless steel or an alloy thereof.

Embodiments may also include one or more of the following features. Thepolymer coating can be formed by spraying a solution of a polymer and adrug to a surface of an endoprosthesis body. The endoprosthesis body canbe a metal. The metal can be stainless steel. The endoprosthesis bodycan be a polymer. The drug can be introduced by coating, dipping, orspraying in a solvent. The polymer coating can be formed by introducinga polymer to the endoprosthesis by dipping, spraying, brushing,pressing, laminating, or pulsed laser deposition (PLD). The drug can beintroduced by PLD. The layer can be formed by PLD. The layer can beformed by magnetron sputtering. The layer can be a metal, such ascopper, gold, silver, ruthenium, titanium, tantalum, platinum,palladium, stainless steel or an alloy thereof. The layer can beceramic. The layer can be IROX. The ceramic can have a smooth globularmorphology to enhance endothelial cell growing over the ceramic. Themethod can further include forming depressions in the polymer coating bylaser irradiation.

Embodiments may include one or more of the following advantages. Stentscan be formed with coatings of a ceramic or metal and a polymer thathave morphologies and/or compositions that enhance therapeuticperformance. In particular, the ceramic or metal can be deposited overthe polymer coating to form a porous coating or membrane that controlsdrug release rate from the polymer as well as reduces the likelihood ofdirect contact of polymer to the body tissue. The over coating ormembrane can be formed of a ceramic, e.g. IROX, which can havetherapeutic advantages such as reducing the likelihood of restenosis andenhancing endothelialization. The morphology of the ceramic coating canbe controlled to tune the therapeutic properties and the porosity of themembrane to provide a desired drug release profile over an extendedperiod. The over coating or membrane may also reduce polymer flaking ordelamination by further fixing it to one side, e.g., the abluminal sideof an endoprosthesis body due to integrity of the over coating. The overcoating can also facilitate deployment from a delivery device duringdeployment by reducing friction between the stent and delivery device.The membrane can be formed by low temperature deposition process, suchas PLD or sputtering, which reduces the likelihood of degradation of theunderlying polymer and/or a drug in the polymer coating. The polymercoating can be selected to accommodate a large quantity of drug and atthe same time be relatively thin. Likewise, the membrane can berelatively thin, so as not to substantially increase the overallthickness of the stent wall.

Still further aspects, features, embodiments, and advantages follow.

DESCRIPTION OF DRAWINGS

FIGS. 1A-1C are longitudinal cross-sectional views illustrating deliveryof a stent in a collapsed state, expansion of the stent, and deploymentof the stent.

FIG. 2 is a perspective view of a stent.

FIG. 3 is a cross-sectional view of region of a stent wall while FIG. 3Ais a greatly enlarged view of region 3A of FIG. 3.

FIGS. 4A-4C are cross-sectional views illustrating a method for forminga stent.

FIG. 5 is a cross-sectional view of another embodiment.

FIG. 6 is a schematic cross-sectional view of a PLD system.

FIGS. 7A-7C are FESEM images: FIGS. 7A and 7B are enlarged plan views ofa stent wall surface, FIG. 7C is an enlarged cross-sectional view of astent wall surface.

FIGS. 8A-8C are schematic views of ceramic morphologies.

FIG. 9 is a schematic top view of a deposition system.

FIG. 10 is an FESEM image of a region of a stent.

DETAILED DESCRIPTION

Referring to FIGS. 1A-1C, a stent 20 is placed over a balloon 12 carriednear a distal end of a catheter 14, and is directed through the lumen 16(FIG. 1A) until the portion carrying the balloon and stent reaches theregion of an occlusion 18. The stent 20 is then radially expanded byinflating the balloon 12 and compressed against the vessel wall with theresult that occlusion 18 is compressed, and the vessel wall surroundingit undergoes a radial expansion (FIG. 1B). The pressure is then releasedfrom the balloon and the catheter is withdrawn from the vessel (FIG.1C).

Referring to FIG. 2, the stent 20 includes a plurality of fenestrations22 defined in a wall 23. Stent 20 includes several surface regions,including an outer, or abluminal, surface 24, an inner, adluminal,surface 26, and a plurality of cut-face surfaces 28. The stent can beballoon expandable, as illustrated above, or a self-expanding stent.Examples of stents are described in Heath '721, supra.

Referring to FIG. 3, a cross-sectional view, a stent wall 23 includes astent body 21 formed, e.g. of a metal, and includes a first coating 25,such as a polymer that includes a drug 27 (e.g. a drug eluting polymer,“DEP”), on the abluminal side 24, and a second coating, such as a porousceramic or metal coating 29 on both the first coating 25 and theadluminal side 26. An interface region (not shown) formed, e.g., of amixture of the polymer and the ceramic or metal may exist between thetwo coatings. The polymer will have substantially no direct contact withbody tissue once the stent is implanted, thus allowing the use of abroader range of polymers, optimized, for example, for drug elutingproperties with less concern for biocompatibility, tissue irritation,tendency to adhere to deployment devices.

Referring to FIG. 3A, the ceramic is deposited as small clusters 28,e.g., 100 nm or less, such as 1-10 nm, and preferably smaller than thegross morphological features of the coating. In embodiments, theclusters amalgamate or bond at contact points forming an almostcontinuous coating with open-cell porous structures or interconnectedpores 31 that serve as passageways between the interior and the exteriorof the ceramic coating. The thickness, the average pore size, and/or thepore to total (solid and pores) volume ratio (e.g., porosity) of theceramic coating 29 can be selected to control drug release profile overtime by, e.g., controlling the diffusion rate of the drug to thesurrounding environment and/or controlling the diffusion rate of bodyfluid to the DEP, when the stent is implanted. In embodiments, thecoating can have a thickness Tc of about a few nanometers (“nm”) to afew hundred nanometers, e.g., of about 10 nm to 500 nm, or about 10-350nm, or about 10-20 nm. In embodiments, the pore size d is selected to beabout 1-20 nm in pore diameter. In embodiments, the porosity is selectedto be about 10% to 40%.

In embodiments, the polymer coating 25 can be a drug eluting polymer(“DEP”), e.g., a biodegradable or non-biodegradable DEP. The coating 25has a thickness Tp of about 100 nm to about 50 μm, e.g., about 200 nm toabout 10 μm, or about 300 nm to about 2 μm, which is selected to controlthe total amount of the releasable drag once the stent is implanted. Inembodiments, the drug content in the DEP is selected to be about 5 toabout 50 weight percent (wt. %), e.g. about 8.8 to about 25 wt. %. Inembodiments, compared to a DEP without coating 29, the polymer can beprovided with higher loadings of drug since the ceramic coating 29modulates the delivery of drug to the body.

In embodiments, the porous coating 29 is formed of a ceramic, such asiridium oxide (“IROX”). Certain ceramics, e.g. oxides, can reducerestenosis through the catalytic reduction of hydrogen peroxide andother precursors to smooth muscle cell proliferation. The oxides canalso encourage endothelial growth to enhance endothelialization of thestent. When a stent is introduced into a biological environment (e.g.,in vivo), one of the initial responses of the human body to theimplantation of a stent, particularly into the blood vessels, is theactivation of leukocytes, white blood cells which are one of theconstituent elements of the circulating blood system. This activationcauses an increase of reactive oxygen compound production. One of thespecies released in this process is hydrogen peroxide, H₂O₂, which isreleased by neutrophil granulocytes, which constitute one of the manytypes of leukocytes. The presence of H₂O₂ may increase proliferation ofsmooth muscle cells and compromise endothelial cell function,stimulating the expression of surface binding proteins which enhance theattachment of more inflammatory cells. A ceramic, such as IROX cancatalytically reduce H₂O₂. The morphology of the ceramic can enhance thecatalytic effect and reduce proliferation of smooth muscle cells. In aparticular embodiment, IROX is selected to form the coating 29, whichcan have therapeutic benefits such as enhancing endothelialization. IROXand other ceramics are discussed further in Alt et al., U.S. Pat. No.5,980,566 and U.S. Ser. No. 10/651,562 filed Aug. 29, 2003.

Referring to FIGS. 4A-4C, cross-section views of a stent strutillustrate exemplary procedures of forming a stent. Referringparticularly to FIGS. 4A and 4B, the stent strut 30 includes a body 21over which is formed a coating 32 of polymer on a selected side of thestrut, such as the abluminal side. Polymeric coating 32 is formed by,e.g., rolling, dipping, spraying, pulsed laser deposition (“PLD”),pressing, brushing, or laminating. In embodiments, the polymer cancontain a drug or a therapeutic agent (circles). The drug may beco-applied to the stent with the polymer by the above-mentionedtechniques or be loaded into the polymeric coating by, e.g., absorptionby the polymer, after the polymer coating is formed on the stent strut.For example, a DEP coating can be formed by spraying the stent with apolymer or a drug saturated solvent which also contains the polymer anddrying under low temperature, e.g. ambient conditions. The DEP coatingcan also be formed by PLD using a drug target and a polymer target. Inother embodiments, the coating 32 may be a polymer precursor, or amixture of a polymer precursor and a drug.

Referring particularly to FIG. 4C, a ceramic coating 34 is depositedconformally over the coating 32 and other surfaces of the strut, such asthe adluminal and cut-face surfaces. The ceramic coating may be appliedby physical deposition processes, such as sputtering or pulsed laserdeposition (“PLD”), or by chemical methods such as sol-gel reactions.

An advantage of having coating 34 surrounding the stent strut asillustrated in FIG. 4C is that the polymer is further fixed or bound tothe abluminal side of the stent due to integrity of the coating 34. As aresult, polymer delamination due to, e.g., sheer force during the stentinsertion in a body passageway, or body liquid seeping to thepolymer-stent interface during or after the insertion, may bediminished. In embodiments, the surface topography of the polymercoating or the ceramic-polymer interface structure is selected to modifydrug release profile. In other embodiments, the stent body is firstcoated with a conformal ceramic coating having, e.g. a high roughnessdefined grain morphology, a polymer coating, including drug is appliedto the high roughness coating on a select portion, e.g. the adluminalportion, and a porous ceramic coating is then applied over the polymer.

Referring particularly to FIG. 5, in embodiments, a series ofdepressions, e.g., wells, in the polymeric coating 33 are created using,e.g., laser ablation or lithography, before depositing a substantiallyconformal ceramic coating over the polymer. In this embodiment, largersurface areas of the polymer are contacted by the ceramic over coatingand thus possible increase of initial drug release rate can be achieved.In an alternative embodiment, the ceramic over coating is not conformal,for example, the ceramic is applied to the polymer in a manner such thatat least one side of the polymer depression, e.g., the side wall, is notcovered by the ceramic, allowing the drug to come out via the polymerwithout being obstructed by the ceramic layer. In such case, anon-porous ceramic over coating can be used instead of the porousceramic material. This partial over coating can be achieved by, e.g.,pulsed-laser depositing the ceramic under an angle such that one side ofthe depressions is not exposed to the ablated ceramic since PLD is adirectional process. It can also be achieved by first depositing theceramic over a flat polymer layer on a stent surface after whichdepressions can be formed using e.g., a excimer or ultrashort laser toselectively remove both the ceramic and the polymer in some regions.

In embodiments, the ceramic is provided over the polymeric coating by atechnique that uses low temperature to reduce the likelihood of damagingthe drug and/or the polymer, such as PLD. Referring to FIG. 6, a PLDsystem 50 includes a chamber 52 in which is provided a target assembly54 and a stent substrate 56, such as a stent body or a pre-stentstructure such as a metal tube. The target assembly includes a targetmaterial 58, such as a ceramic (e.g., IROX) or a precursor to a ceramic(e.g., iridium metal). Laser energy (double arrows) is selectivelydirected onto the target materials to cause the target materials to beablated and sputtered from the target assembly. The sputtered materialis imparted with kinetic energy in the ablation process such that thematerial is transported within the chamber (single arrows) and depositedon the stent 56. The target assembly may include more than one target(e.g., two targets) so that different materials, e.g., drugs, ceramicsor mixtures of a ceramic and a polymer or of a polymer and a drug, canbe deposited simultaneously or sequentially on the stent 56 forcontrolling drug release profiles. In addition, the temperature of thedeposited material can be controlled by heating, e.g. using an infraredsource (squiggly arrows).

The porosity of the ceramic can be controlled by selecting themorphology, crystallinity, thickness, and size of the clusters ablatedand deposited. Higher crystallinity, more defined grain morphologies,and thinner coatings provide greater porosity. Coating thickness iscontrolled by controlling deposition time. Higher laser energies canprovide larger cluster sizes.

In certain embodiments, if more than one targets, e.g., a polymer targetand a ceramic target are needed for deposition, the composition of thedeposited material is selected by controlling the exposure of the targetmaterials to laser energy. For example, to deposit pure polymer or pureceramic, only the polymer or ceramic material is exposed to laserenergy. To deposit a composite layer of ceramic and polymer, bothmaterials are exposed simultaneously or alternately exposed in rapidsuccession. The relative amount of polymer and ceramic is controlled bythe laser energy and/or exposure time. In embodiments, the ceramic orpolymer is deposited as small clusters, e.g., 100 nm or less, such as1-10 nm, and preferably smaller than the gross morphological features ofthe layers. In embodiments, the clusters bond at contact points forminga continuous coating that is an amalgamation of the clusters. Themolecular weight of the polymer can be controlled by selecting the laserwavelength and energy. In the ablation process, energy absorbed by thetarget can result in cleavage of covalent bonds in polymers, such thatthe chain lengths and molecular weight of the polymer in the target isreduced in the deposition material. The efficiency of the cleavageprocess can be enhanced by selecting a laser wavelength that the polymerabsorbs strongly. In addition, at higher energies, the size of ablatedclusters is increased, with less overall chain cleavage.

In particular embodiments, the laser energy is produced by an excimerlaser operating in the ultraviolet, e.g. at a wavelength of about 248nm. The laser energy is about 100-700 mJ, the fluence is in the range ofabout 10 to 50 mJ/cm2. The background pressure is in the range of about1E-5 mbar to 1 mbar. The background gas includes oxygen. The substratetemperature is also controlled. The temperature of the substrate isbetween 0 to 150° C. during deposition. Substrate temperature can becontrolled by directing an infrared beam onto the substrate duringdeposition using, e.g. a halogen source. The temperature is measured bymounting a heat sensor in the beam adjacent the substrate. Thetemperature can be varied to control the morphology of the ceramic andmelting of the polymer. The selective sputtering of the ceramic orpolymer is controlled by mounting the target material on a movingassembly that can alternately bring the materials into the path of thelaser. Alternatively, a beam splitter and shutter can be used toalternatively or simultaneously expose multiple materials. PLDdeposition services are available from Axyntec, Augsburg, Germany.Suitable ceramics include metal oxides and nitrides, such as of iridium,zirconium, titanium, hafnium, niobium, tantalum, ruthenium, platinum andaluminum. In embodiments, the thickness of the coatings is in the rangeof about 10 m to about 2 um, e.g. 100 nm to 500 nm. Pulsed laserdeposition is also described in application U.S. Ser. No. 11/752,736,filed May 23, 2007 . The target can be a pure metal, e.g. IR target oriridium oxide in the form of compressed powder. The polymer, e.g.including drug, can also be deposited by PLA. In embodiments, thepolymer is SIBS and the drug is paclitaxal at e.g. 8.8%. The laser poweris 100 to 250 mn and the pressure between about 0.04 mbar and 0.2 mbar.

In other embodiments, another physical vapor deposition (“PVD”) processis selected such as magnetron sputtering e.g. an iridium target under anoxygen atmosphere or an IROX target. Sputtering deposition is describedin application U.S. Ser. No. 11/752,772, filed May 23, 2007 . In thecase of a ceramic or a metal over coating, the porosity can be furthercontrolled by laser ablating apertures into the layer with, e.g. a U.V.laser.

Referring to FIGS. 7A and 7B, the morphology of the ceramic can bevaried between relatively rough surfaces and relatively smooth surfaces,which can each provide particular mechanical and therapeutic advantages,such as a controlled porosity to modulate drug release from the polymerlayer. Referring particularly to FIG. 7A, a ceramic coating can have amorphology characterized by defined grains and high roughness. Referringparticularly to FIG. 7B, a ceramic coating can have a morphologycharacterized by a higher coverage, globular surface of generally lowerroughness. The defined grain, high roughness morphology provides a highsurface area characterized by crevices between and around spaced grainsinto which the polymer coating can be deposited and interlock to thesurface, greatly enhancing adhesion. Defined grain morphologies alsoallow for greater freedom of motion and are less likely to fracture asthe stent is flexed in use and thus the matrix coating resistsdelamination of the ceramic from an underlying surface and reducesdelamination of a possible overlaying coating. The stresses caused byflexure of the stent, during expansion or contraction of the stent or asthe stent is delivered through a tortuously curved body lumen increaseas a function of the distance from the stent axis. As a result, inembodiments, a morphology with defined grains is particularly desirableon abluminal regions of the stent or at other high stress points, suchas the regions adjacent fenestrations which undergo greater flexureduring expansion or contraction. Smoother globular surface morphologyprovides a surface which is tuned to facilitate endothelial growth byselection of its chemical composition and/or morphological features.Certain ceramics, e.g. oxides, can reduce restenosis through thecatalytic reduction of hydrogen peroxide and other precursors to smoothmuscle cell proliferation. The oxides can also encourage endothelialcell growth to enhance endothelialization of the stent. As discussedabove, when a stent, is introduced into a biological environment (e.g.,in vivo), one of the initial responses of the human body to theimplantation of a stent, particularly into the blood vessels, is theactivation of white blood cells. This activation causes a release ofhydrogen peroxide, H₂O₂. The presence of H₂O₂ may increase proliferationof smooth muscle cells and compromise endothelial cell function,stimulating the expression of surface binding proteins which enhance theattachment of more inflammatory cells. A ceramic, such as IROX cancatalytically reduce H₂O₂. The smoother globular surface morphology ofthe ceramic can enhance the catalytic effect and enhance growth ofendothelial cells.

Referring particularly to FIG. 7C, a cross-sectional view of the ceramiclayer with surface morphology shown in FIG. 7B, channels formed ofinterconnected pores in the ceramic are visible. In embodiments, thechannels have a diameter selectively controlled by deposition parametersas discussed above. The bigger the diameter, the faster the drug releaserate. In particular embodiments, the channel diameter is selected to beabout 10 nm or less to control the drug release over a extended periodof time.

The morphology of the ceramic is controlled by controlling the energy ofthe sputtered clusters on the stent substrate. Higher energies andhigher temperatures result in defined grain, higher roughness surfaces.Higher energies are provided by increasing the temperature of theceramic on the substrate, e.g. by heating the substrate or heating theceramic with infrared radiation. In embodiments, defined grainmorphologies are formed at temperatures of about 250° C. or greater.Globular morphologies are formed at lower temperatures, e.g. ambienttemperatures without external factors. The heating enhances theformation of a more crystalline ceramic, which forms the grains.Intermediate morphologies are formed at intermediate values of theseparameters. The composition of the ceramic can also be varied. Forexample, oxygen content can be increased by providing oxygen gas in thechamber.

The morphology of the surface of the ceramic is characterized by itsvisual appearance, its roughness, and/or the size and arrangement ofparticular morphological features such as local maxima. In embodiments,the surface is characterized by definable sub-micron sized grains.Referring particularly to FIG. 7A, for example, in embodiments, thegrains have a length, L, of the of about 50 to 500 nm, e.g. about100-300 nm, and a width, W, of about 5 nm to 50 nm, e.g. about 10-15 nm.The grains have an aspect ratio (length to width) of about 5:1 or more,e.g. 10:1 to 20:1. The grains overlap in one or more layers. Theseparation between grains can be about 1-50 nm. In particularembodiments, the grains resemble rice grains.

Referring particularly to FIG. 7B, in embodiments, the surface ischaracterized by a more continuous surface having a series of shallowglobular features. The globular features are closely adjacent with anarrow minima between features. In embodiments, the surface resembles anorange peel. The diameter of the globular features is about 100 nm orless, and the depth of the minima, or the height of the maxima of theglobular function is e.g. about 50 nm or less, e.g. about 20 nm or less.In other embodiments, the surface has characteristics between highaspect ratio definable grains and the more continuous globular surfaceand/or has a combination of these characteristics. For example, themorphology can include a substantially globular base layer and arelatively low density of defined grains. In other embodiments, thesurface can include low aspect ratio, thin planar flakes. The morphologytype is visible in FESEM images at 50 KX.

Referring to FIGS. 8A-8C, morphologies are also characterized by thesize and arrangement of morphological features such as the spacing,height and width of local morphological maxima. Referring particularlyto FIG. 5A, a coating 40 on a substrate 42 is characterized by thecenter-to-center distance and/or height, and/or diameter and/or densityof local maxima. In particular embodiments, the average height, distanceand diameter are in the range of about 400 nm or less, e.g. about 20-200nm. In particular, the average center-to-center distance is about 0.5 to2× the diameter.

Referring to FIG. 8B, in particular embodiments, the morphology type isa globular morphology, the width of local maxima is in the range ofabout 100 nm or less and the peak height is about 20 nm or less. Inparticular embodiments, the ceramic has a peak height of less than about5 nm, e.g., about 1-5 nm, and/or a peak distance less than about 15 m,e.g., about 10-15 nm. Referring to FIG. 8C, in embodiments, themorphology is defined as a grain type morphology. The width of localmaxima is about 400 nm or less, e.g. about 100-400 nm, and the height oflocal maxima is about 400 nm or less, e.g. about 100-400 nm. Asillustrated in FIGS. 8B and 8C, the select morphologies of the ceramiccan be formed on a thin layer of substantially uniform, generallyamorphous IROX, which is in turn formed on a layer of iridium metal,which is in turn deposited on a metal substrate, such as titanium orstainless steel. The spacing, height and width parameters can becalculated from AFM data.

The roughness of the surface is characterized by the average roughness,Sa, the root mean square roughness, Sq, and/or the developed interfacialarea ratio, Sdr. The Sa and Sq parameters represent an overall measureof the texture of the surface. Sa and Sq are relatively insensitive indifferentiating peaks, valleys and the spacing of the various texturefeatures. Surfaces with different visual morphologies can have similarSa and Sq values. For a surface type, the Sa and Sq parameters indicatesignificant deviations in the texture characteristics. Sdr is expressedas the percentage of additional surface area contributed by the textureas compared to an ideal plane the size of the measurement region. Sdrfurther differentiates surfaces of similar amplitudes and averageroughness. Typically Sdr will increase with the spatial intricacy of thetexture whether or not Sa changes.

In embodiments, the ceramic has a defined grain type morphology. The Sdris about 30 or more, e.g. about 40 to 60. In addition or in thealternative, the morphology has an Sq of about 15 or more, e.g. about 20to 30. In embodiments, the Sdr is about 100 or more and the Sq is about15 or more. In other embodiments, the ceramic has a globular typesurface morphology. The Sdr is about 20 or less, e.g. about 8 to 15. TheSq is about 15 or less, e.g. about less than 8 to 14. In still otherembodiments, the ceramic has a morphology between the defined grain andthe globular surface, and Sdr and Sq values between the ranges above,e.g. an Sdr of about 1 to 200 and/or an Sq of about 1 to 30. The Sa, Sq,and Sdr can be calculated from AFM data.

The morphology of the ceramic coating can exhibit high uniformity. Theuniformity provides predictable, tuned therapeutic and mechanicalperformance of the ceramic. The uniformity of the morphology ascharacterized by Sa, Sq or Sdr and/or average peak spacing parameterscan be within about +/−20% or less, e.g. +/−10% or less within a tamsquare. In a given stent region, the uniformity is within about +/−10%,e.g. about +/−1%. For example, in embodiments, the ceramic exhibits highuniformity over an entire surface region of stent, such as the entireabluminal or adluminal surface, or a portion of a surface region, suchas the center 25% or 50% of the surface region. The uniformity isexpressed as standard deviation. Uniformity in a region of a stent canbe determined by determining the average in five randomly chosen 1 μmsquare regions and calculating the standard deviation. Uniformity of amorphology type in a region is determined by inspection of FESEM data at50 kx.

The ceramics are also characterized by surface composition, compositionas a function of depth, and crystallinity. In particular, the amounts ofoxygen or nitride in the ceramic is selected for a desired catalyticeffect on, e.g., the reduction of H₂O₂ in biological processes. Thecomposition of metal oxide or nitride ceramics can be determined as aratio of the oxide or nitride to the base metal. In particularembodiments, the ratio is about 2 to 1 or greater, e.g. about 3 to 1 orgreater, indicating high oxygen content of the surface. In otherembodiments, the ratio is about 1 to 1 or less, e.g. about 1 to 2 orless, indicating a relatively low oxygen composition. In particularembodiments, low oxygen content globular morphologies are formed toenhance endothelialization. In other embodiments, high oxygen contentdefined grain morphologies are formed, e.g., to enhance adhesion andcatalytic reduction. Composition can be determined by x-rayphotoelectron spectroscopy (XPS). Depth studies are conducted by XPSafter FAB sputtering. The crystalline nature of the ceramic can becharacterized by crystal shapes as viewed in FESEM images, or Millerindices as determined by x-ray diction. In embodiments, defined grainmorphologies have a Miller index of <101>. Globular materials haveblended amorphous and crystalline phases that vary with oxygen content.Higher oxygen content typically indicates greater crystallinity. Furtherdiscussion of ceramics and ceramic morphology and computation ofroughness parameters is provided in U.S. Ser. No. 11/752,736, filed May23, 2007, U.S. Ser. No. 11/752,772, filed May 23, 2007, and appendices.

In certain embodiments, referring back to FIG. 3, the second coating 29can be a porous metallic coating, formed for example, by using ananocluster deposition system (“NCDS”). Referring particularly to FIG.9, an NCDS 100 includes several differentially pumped chambers: acluster source chamber 120 and a deposition chamber 140. The system mayalso have a load lock for rapid substrate change; a time of flight massspectrometer (TOF) chamber (not shown) for analysis of the cluster sizedistribution; and/or an XPS system for elemental analysis with aseparate transfer chamber (not shown). In the cluster source chamber,nanoparticles or clusters, such as copper, gold, ruthenium, stainlesssteel, iron, magnesium, and tungsten can be produced by high-pressuremagnetron sputtering, for example, operating a magnetron head 122 in apressure of about 0.1 to a few millibars with a flow of a working gas,e.g., argon provided by “Gas Source 1” shown in the figure. The relativehigh pressure allows the sputtered atoms or small clusters to aggregateor condensate in an aggregation zone 124 to form nanoparticles orclusters of desired size before they are transported to the depositionchamber. The clusters are carried by the flowing gas through an aperture112, whose diameter can be varied during operation of the clustersource. After aperture 112, the clusters enter a differential pumpingzone 126, where most of the carrier gas, atoms and/or lighter clustersare pumped away through vacuum port 130, while the heavier clusters passthrough a further aperture 110 into the deposition chamber. Clusters arethen electrically separated by ion optics 150 into a neutral (n) and acharged (c) beam. The charged clusters of one polarity can beaccelerated up to about 50 keV and impinge on the substrate holder 128,which is connected to a voltage source 160 and can be moved horizontally(double-head arrow 101) and rotated (arrow 103) by a small motor (notshown). The charged clusters or nanoparticles generated may further bemass selected by a linear quadrupole (not shown) and selectivelydeposited on the substrate. For example, typical diameter of theclusters generated can be about 0.7 to 20 nm and size distribution ofthe clusters can be selectively narrowed to about +/−20%, or even to+/−2%.

The kinetic energy (e.g., about 100 V to 50 keV) of the clusters partlycontrolled by the applied voltage on the substrate holder may induceclusters melting upon impact the substrate and may cause damage to thepolymeric substrate due to local heating. In embodiments, a firstcollection of clusters are deposited with a kinetic energy, e.g., 0.1keV, that is high enough for the clusters to adhere to or penetrate thepolymer substrate but substantially causes no heat damage to the polymerand/or the drug incorporated in the polymer. A second collection ofclusters with higher kinetic energy, e.g., 5 keV, can then be depositedon top of the first collection. In embodiments, the magnetron head canbe moved within the aggregation zone. Reducing the distance from themagnetron head to the first aperture reduces the distance and timewhereby condensation can occur so the average cluster size is reduced.In embodiments, several other gases (shown as “Gas Source 2”) can beadded into the source chamber. For example, introducing helium can leadto a reduction of the cluster size while introducing oxygen or nitrogencan lead to generation of ceramic clusters or nanoparticles by reactivesputtering and ceramic coating on the polymer substrate. Nanocluster ornanoparticle deposition services are available, e.g., from MantisDeposition Ltd., England (http://www.mantisdeposition.com) and therelevant techniques are further disclosed by Weber et al., ProvisionalApplication No. 60/857,849, A. H. Kean et al., Mantis Deposition Ltd.,NSTI Nano Tech 2006, Boston, May 7-11, 2006, in Y. Qiang et al., Surfaceand Coating Technology, 100-101, 27-32 (1998) and in Kraft et al.,Surface and Coating Technology, 158-159, 131-135 (2002).

In embodiments, the ceramic or metal is adhered only on the abluminalsurface of the stent. This construction may be accomplished by, e.g.coating the stent before forming the fenestrations, as described ine.g., Weber, U.S. Pat. No. 6,517,888. In other embodiments, the ceramicor metal is adhered only on abluminal and cut-face surfaces of thestent. This construction may be accomplished by, e.g., coating a stentcontaining a mandrel, which shields the luminal surfaces. Masks can beused to shield portions of the stent. In embodiments, the stent metalcan be stainless steel, chrome, nickel, cobalt, tantalum, superelasticalloys such as nitinol, cobalt chromium, MP35N, and other metals.Suitable stent materials and stent designs are described in Heath '721,supra. Other suitable ceramics include metal oxides and nitrides, suchas of iridium, zirconium, titanium, hafnium, niobium, tantalum,ruthenium, platinum and aluminum. The ceramic can be crystalline, partlycrystalline or amorphous. The ceramic can be formed entirely ofinorganic materials or a blend of inorganic and organic material (e.g. apolymer). In other embodiments, the morphologies described herein can beformed of metal. As discussed above, different ceramic materials can beprovided in different regions of a stent. For example, differentmaterials may be provided on different stent surfaces. A rougher,defined grain material may be provided on the abluminal surface to, e.g.enhance porosity or adhesion to the polymer while a smooth globularmaterial can be provided on the adluminal surface to enhanceendothelialization. In yet some embodiments, a material of a definedgrain morphology may be provided first on the stent surface to, e.g.enhance adhesion of the polymer while a smooth globular material can beprovided on top of the polymer to enhance endothelialization.

The ceramic material can also be selected for compatibility with aparticular polymer coating to, e.g. enhance adhesion. For example, for ahydrophilic polymer, the surface chemistry of the ceramic is made morehydrophilic by e.g., increasing the oxygen content, which increasespolar oxygen moieties, such as OH groups. Suitable drug eluting polymersmay be hydrophilic or hydrophobic. Suitable polymers include, forexample, polycarboxylic acids, cellulosic polymers, including celluloseacetate and cellulose nitrate, gelatin, polyvinylpyrrolidone,cross-linked polyvinylpyrrolidone, polyanhydrides including maleicanhydride polymers, polyamides, polyvinyl alcohols, copolymers of vinylmonomers such as EVA, polyvinyl ethers, polyvinyl aromatics such aspolystyrene and copolymers thereof with other vinyl monomers such asisobutylene, isoprene and butadiene, for example,styrene-isobutylene-styrene (SIBS), styrene-isoprene-styrene (SIS)copolymers, styrene-butadiene-styrene (SBS) copolymers, polyethyleneoxides, glycosaminoglycans, polysaccharides, polyesters includingpolyethylene terephthalate, polybutylene succinate (PBS), andpolybutylene suucinate adipate (PBSA), polyacrylamides, polyethers,polyether sulfone, polycarbonate, polyalkylenes including polypropylene,polyethylene and high molecular weight polyethylene, halogeneratedpolyalkylenes including polytetrafluoroethylene, natural and syntheticrubbers including polyisoprene, polybutadiene, polyisobutylene andcopolymers thereof with other vinyl monomers such as styrene,polyurethanes, polyorthoesters, proteins, polypeptides, silicones,siloxane polymers, polylactic acid, polyglycolic acid, polycaprolactone,polyhydroxybutyrate valerate and blends and copolymers thereof as wellas other biodegradable, bioabsorbable and biostable polymers andcopolymers. Coatings from polymer dispersions such as polyurethanedispersions (BAYHDROL®, etc.) and acrylic latex dispersions are alsowithin the scope of the present disclosure. The polymer may be a proteinpolymer, fibrin, collagen and derivatives thereof, polysaccharides suchas celluloses, starches, dextrans, alginates and derivatives of thesepolysaccharides, an extracellular matrix component, hyaluronic acid, oranother biologic agent or a suitable mixture of any of these, forexample. U.S. Pat. No. 5,091,205 describes medical devices coated withone or more polyiocyanates such that the devices become instantlylubricious when exposed to body fluids. In embodiments, a suitablepolymer is polyacrylic acid, available as HYDROPLUS®. (Boston ScientificCorporation, Natick, Mass.), and described in U.S. Pat. No. 5,091,205,the disclosure of which is hereby incorporated herein by reference.Another polymer can be a copolymer of polylactic acid andpolycaprolactone. The polymer can be biostable or biodegradable.Suitable polymers are discussed in U.S. Publication No. 2006/0038027.

In embodiments, the polymer is capable of absorbing a substantial amountof drug solution. In embodiments, when applied as a coating on a medicaldevice, the dry polymer is typically on the order of from about 1 toabout 50 microns thick, preferably about 1 to 10 microns thick, and morepreferably about 2 to 5 microns. In embodiments, very thin polymercoatings, e.g., of about 0.2-0.3 microns and much thicker coatings,e.g., more than 10 microns, are also possible. In some embodiments,multiple layers of polymer coating can be provided onto a medicaldevice. Such multiple layers are of the same or different polymermaterials. Such multiple layers can contain different drugs in eachlayer, or some of the multiple layers may not contain any drugs.Suitable DEP coating are further disclosed in U.S. Pat. Nos. 5,605,696and 5,447,724. In certain embodiments, the polymer can only act as amembrane to regulate drug release. For example, drug particles can firstbe applied to the stent, then a layer of polymer can be applied on topof the drugs and between the drugs and the ceramic coating to function afirst drug release regulating layer while the ceramic coating functionsas a second drug release regulating layer.

The terms “therapeutic agent”, “pharmaceutically active agent”,“pharmaceutically active material”, “pharmaceutically activeingredient”, “drug” and other related terms may be used interchangeablyherein and include, but are not limited to, small organic molecules,peptides, oligopeptides, proteins, nucleic acids, oligonucleotides,genetic therapeutic agents, non-genetic therapeutic agents, vectors fordelivery of genetic therapeutic agents, cells, and therapeutic agentsidentified as candidates for vascular treatment regimens, for example,as agents that reduce or inhibit restenosis. By small organic moleculeis meant an organic molecule having 50 or fewer carbon atoms, and fewerthan 100 non-hydrogen atoms in total.

Exemplary non-genetic therapeutic agents for use in conjunction with thepresent invention include: (a) anti-thrombotic agents such as heparin,heparin derivatives, urokinase, and PPack (dextrophenylalanine prolinearginine chloromethylketone); (b) anti-inflammatory agents such asdexamethasone, prednisolone, corticosterone, budesonide, estrogen,sulfasalazine and mesalamine; (c)antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel,5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones,endostatin, angiostatin, angiopeptin, monoclonal antibodies capable ofblocking smooth muscle cell proliferation, and thymidine kinaseinhibitors; (d) anesthetic agents such as lidocaine, bupivacaine andropivacaine; (e) anti-coagulants such as D-Phe-Pro-Arg chloromethylketone, an RGD peptide-containing compound, heparin, hirudin,antithrombin compounds, platelet receptor antagonists, anti-thrombinantibodies, anti-platelet receptor antibodies, aspirin, prostaglandininhibitors, platelet inhibitors and tick antiplatelet peptides; (f)vascular cell growth promoters such as growth factors, transcriptionalactivators, and translational promotors; (g) vascular cell growthinhibitors such as growth factor inhibitors, growth factor receptorantagonists, transcriptional repressors, translational repressors,replication inhibitors, inhibitory antibodies, antibodies directedagainst growth factors, bifunctional molecules consisting of a growthfactor and a cytotoxin, bifunctional molecules consisting of an antibodyand a cytotoxin; (h) protein kinase and tyrosine kinase inhibitors(e.g., tyrphostins, genistein, quinoxalines); (i) prostacyclin analogs;(j) cholesterol-lowering agents; (k) angiopoietins; (l) antimicrobialagents such as triclosan, cephalosporins, aminoglycosides andnitrofurantoin; (m) cytotoxic agents, cytostatic agents and cellproliferation affectors; (n) vasodilating agents; (o) agents thatinterfere with endogenous vasoactive mechanisms; p) inhibitors ofleukocyte recruitment, such as monoclonal antibodies; (q) cytokines; (r)hormones; (s) inhibitors of HSP 90 protein (i.e., Heat Shock Protein,which is a molecular chaperone or housekeeping protein and is needed forthe stability and function of other client proteins/signal transductionproteins responsible for growth and survival of cells) includinggeldanamycin, (t) alpha receptor antagonist (such as doxazosin,Tamsulosin) and beta receptor agonists (such as dobutamine, salmeterol),beta receptor antagonist (such as atenolol, metaprolol, butoxamine),angiotensin-II receptor antagonists (such as losartan, valsartan,irbesartan, candesartan and telmisartan), and antispasmodic drugs (suchas oxybutynin chloride, flavoxate, tolterodine, hyoscyamine sulfate,diclomine), (u) bARKct inhibitors, (v) phospholamban inhibitors, (w)Serca 2 gene/protein, (x) immune response modifiers includingaminoquizolines, for instance, imidazoquinolines such as resiquimod andimiquimod, and (y) human apolioproteins (e.g., AI, AII, AIII, AIV, AV,etc.).

Specific examples of non-genetic therapeutic agents include paclitaxel,(including particulate forms thereof, for instance, protein-boundpaclitaxel particles such as albumin-bound paclitaxel nanoparticles,e.g., ABRAXANE), sirolimus, everolimus, tacrolimus, Epo D,dexamethasone, estadiol, halofuginone, cilostazole, geldanamycin,ABT-578 (Abbott Laboratories), trapidil, liprostin, Actinomcin D,Resten-NG, Ap-17, abciximab, clopidogrel, Ridogrel, beta-blockers,bARKct inhibitors, phospholamban inhibitors, Serca 2 gene/protein,imiquimod, human apolioproteins (e.g., AI-AV), growth factors (e.g.,VEGF-2), as well a derivatives of the forgoing, among others.

Exemplary genetic therapeutic agents for use in conjunction with thepresent invention include anti-sense DNA and RNA as well as DNA codingfor the various proteins (as well as the proteins themselves): (a)anti-sense RNA, (b) tRNA or rRNA to replace defective or deficientendogenous molecules, (c) angiogenic and other factors including growthfactors such as acidic and basic fibroblast growth factors, vascularendothelial growth factor, endothelial mitogenic growth factors,epidermal growth factor, transforming growth factor α and β,platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor α, hepatocyte growth factor andinsulin-like growth factor, (d) cell cycle inhibitors including CDinhibitors, and (e) thymidine kinase (“TK”) and other agents useful forinterfering with cell proliferation. Also of interest is DNA encodingfor the family of bone morphogenic proteins (“BMP's”), including BMP-2,BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10,BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16. Currently preferredBMP's are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7. Thesedimeric proteins can be provided as homodimers, heterodimers, orcombinations thereof, alone or together with other molecules.Alternatively, or in addition, molecules capable of inducing an upstreamor downstream effect of a BMP can be provided. Such molecules includeany of the “hedgehog” proteins, or the DNA's encoding them.

Vectors for delivery of genetic therapeutic agents include viral vectorssuch as adenoviruses, gutted adenoviruses, adeno-associated virus,retroviruses, alpha virus (Semliki Forest, Sindbis, etc.), lentiviruses,herpes simplex virus, replication competent viruses (e.g., ONYX-015) andhybrid vectors; and non-viral vectors such as artificial chromosomes andmini-chromosomes, plasmid DNA vectors (e.g., pCOR), cationic polymers(e.g., polyethyleneimine, polyethyleneimine (PEI)), graft copolymers(e.g., polyether-PEI and polyethylene oxide-PEI), neutral polymers PVP,SP1017 (SUPRATEK), lipids such as cationic lipids, liposomes,lipoplexes, nanoparticles, or microparticles, with and without targetingsequences such as the protein transduction domain (PTD).

Cells for use in conjunction with the present invention include cells ofhuman origin (autologous or allogeneic), including whole bone marrow,bone marrow derived mono-nuclear cells, progenitor cells (e.g.,endothelial progenitor cells), stem cells (e.g., mesenchymal,hematopoietic, neuronal), pluripotent stem cells, fibroblasts,myoblasts, satellite cells, pericytes, cardiomyocytes, skeletal myocytesor macrophage, or from an animal, bacterial or fungal source(xenogeneic), which can be genetically engineered, if desired, todeliver proteins of interest.

Numerous therapeutic agents, not necessarily exclusive of those listedabove, have been identified as candidates for vascular treatmentregimens, for example, as agents targeting restenosis. Such agents areuseful for the practice of the present invention and include one or moreof the following: (a) Ca-channel blockers including benzothiazapinessuch as diltiazem and clentiazem, dihydropyridines such as nifedipine,amlodipine and nicardapine, and phenylalkylamines such as verapamil, (b)serotonin pathway modulators including: 5-HT antagonists such asketanserin and naftidrofuryl, as well as 5-HT uptake inhibitors such asfluoxetine, (c) cyclic nucleotide pathway agents includingphosphodiesterase inhibitors such as cilostazole and dipyridamole,adenylate/Guanylate cyclase stimulants such as forskolin, as well asadenosine analogs, (d) catecholamine modulators including α-antagonistssuch as prazosin and bunazosine, β-antagonists such as propranolol andα/β-antagonists such as labetalol and carvedilol, (e) endothelinreceptor antagonists, (f) nitric oxide donors/releasing moleculesincluding organic nitrates/nitrites such as nitroglycerin, isosorbidedinitrate and amyl nitrite, inorganic nitroso compounds such as sodiumnitroprusside, sydnonimines such as molsidomine and linsidomine,nonoates such as diazenium diolates and NO adducts of alkanediamines,S-nitroso compounds including low molecular weight compounds (e.g.,S-nitroso derivatives of captopril, glutathione and N-acetylpenicillamine) and high molecular weight compounds (e.g., S-nitrosoderivatives of proteins, peptides, oligosaccharides, polysaccharides,synthetic polymers/oligomers and natural polymers/oligomers), as well asC-nitroso-compounds, O-nitroso-compounds, N-nitroso-compounds andL-arginine, (g) ACE inhibitors such as cilazapril, fosinopril andenalapril, (h) ATII-receptor antagonists such as saralasin and losartin,(i) platelet adhesion inhibitors such as albumin and polyethylene oxide,(j) platelet aggregation inhibitors including cilostazole, aspirin andthienopyridine (ticlopidine, clopidogrel) and GP IIb/IIIa inhibitorssuch as abciximab, epitifibatide and tirofiban, (k) coagulation pathwaymodulators including heparinoids such as heparin, low molecular weightheparin, dextran sulfate and f-cyclodextrin tetradecasulfate, thrombininhibitors such as hirudin, hirulog,PPACK(D-phe-L-propyl-L-arg-chloromethylketone) and argatroban, FXainhibitors such as antistatin and TAP (tick anticoagulant peptide),Vitamin K inhibitors such as warfarin, as well as activated protein C,(l) cyclooxygenase pathway inhibitors such as aspirin, ibuprofen,flurbiprofen, indomethacin and sulfinpyrazone, (m) natural and syntheticcorticosteroids such as dexamethasone, prednisolone, methprednisoloneand hydrocortisone, (n) lipoxygenase pathway inhibitors such asnordihydroguairetic acid and caffeic acid, (o) leukotriene receptorantagonists, (p) antagonists of E- and P-selectins, (q) inhibitors ofVCAM-1 and ICAM-1 interactions, (r) prostaglandins and analogs thereofincluding prostaglandins such as PGE1 and PGI2 and prostacyclin analogssuch as ciprostene, epoprostenol, carbacyclin, iloprost and beraprost,(s) macrophage activation preventers including bisphosphonates, (t)HMG-CoA reductase inhibitors such as lovastatin, pravastatin,fluvastatin, simvastatin and cerivastatin, (u) fish oils andomega-3-fatty acids, (v) free-radical scavengers/antioxidants such asprobucol, vitamins C and E, ebselen, trans-retinoic acid and SOD mimics,(w) agents affecting various growth factors including FGF pathway agentssuch as bFGF antibodies and chimeric fusion proteins, PDGF receptorantagonists such as trapidil, IGF pathway agents including somatostatinanalogs such as angiopeptin and ocreotide, TGF-β pathway agents such aspolyanionic agents (heparin, fucoidin), decorin, and TGF-β antibodies,EGF pathway agents such as EGF antibodies, receptor antagonists andchimeric fusion proteins, TNF-α pathway agents such as thalidomide andanalogs thereof, Thromboxane A2 (TXA2) pathway modulators such assulotroban, vapiprost, dazoxiben and ridogrel, as well as proteintyrosine kinase inhibitors such as tyrphostin, genistein and quinoxalinederivatives, (x) MMP pathway inhibitors such as marimastat, ilomastatand metastat, (y) cell motility inhibitors such as cytochalasin B, (z)antiproliferative/antineoplastic agents including antimetabolites suchas purine analogs (e.g., 6-mercaptopurine or cladribine, which is achlorinated purine nucleoside analog), pyrimidine analogs (e.g.,cytarabine and 5-fluorouracil) and methotrexate, nitrogen mustards,alkyl sulfonates, ethylenimines, antibiotics (e.g., daunorubicin,doxorubicin, macrolide antibiotics such as erythromycin), nitrosoureas,cisplatin, agents affecting microtubule dynamics (e.g., vinblastine,vincristine, colchicine, Epo D, paclitaxel and epothilone), caspaseactivators, proteasome inhibitors, angiogenesis inhibitors (e.g.,endostatin, angiostatin and squalamine), rapamycin, cerivastatin,flavopiridol and suramin, (aa) matrix deposition/organization pathwayinhibitors such as halofuginone or other quinazolinone derivatives andtrailast (bb) endothelialization facilitators such as VEGF and RGDpeptide, and (cc) blood rheology modulators such as pentoxifylline.

Further additional therapeutic agents include immunosuppressents such assirolimus and antibiotics such as macrolide antibiotics, evorolimus, andTacrolimus for the practice of the present invention are also disclosedin U.S. Pat. No. 5,733,925.

Where a therapeutic agent is included, a wide range of therapeutic agentloadings can be used in conjunction with the medical devices of thepresent invention, with the therapeutically effective amount beingreadily determined by those of ordinary skill in the art and ultimatelydepending, for example, upon the condition to be treated, the age, sexand condition of the patient, the nature of the therapeutic agent, thenature of the ceramic region(s), and/or the nature of the medicaldevice, among other factors.

EXAMPLE

In a particular embodiment a 1% toluene solution of SIBS with 8.8 wt. %paclitaxel was sprayed onto a stainless steel stent with masks on itsadluminal and cut-face surfaces until the thickness reached a desiredvalue, e.g., 10 microns. The stent coated with DEP was then dried inair. The drug content of the dry DEP coating was about 8.8% by weight.Subsequently, the DEP-coated stent was mount in an Axplorer PLD systemby Axyntec, Augsburg, Germany. An iridium (99.9 wt. %) target wasablated by a 248 nm laser of 10 ns pulse at an energy of 600 ml, basepressure of 0.8 mbar oxygen, and substrate temperature of 50 degrees ofCelsius. The resultant IROX layer had a thickness of about 15 nm to 150nm.

Referring to FIG. 10, a field emission scanning electron microscopy(“FESEM”) image of the surface of a strut of a stainless steel stentprocessed with the method disclosed in EXAMPLE is shown. As shown inFIG. 10, about 10-15 nm thick of IROX covers the stent surface,underneath which is about several microns thick of SIBS/paclitaxel(“PTX”).

In further embodiments, the polymeric coating may incorporate magneticparticles, e.g., nanoparticles. The embodiments may have one or moreadditional following advantages, including that the release profile of atherapeutic agent from an endoprosthesis can be controlled throughnon-invasive means, e.g., a magnetic field. The magnetic field can beused to selectively agitate the particles, to modify drug release fromthe polymeric coating. Use of magnetic particles is described further inU.S. Provisional Application No. 60/845,136, filed Sep. 15, 2006.

Any stent described herein can be dyed or rendered radiopaque byaddition of, e.g., radiopaque materials such as barium sulfate, platinumor gold, or by coating with a radiopaque material. The stent can include(e.g., be manufactured from) metallic materials, e.g., biostablemetallic materials such as stainless steel (e.g., 316L, BioDur® 108 (UNSS29108), and 304L stainless steel, and an alloy including stainlesssteel and 5-60% by weight of one or more radiopaque elements (e.g., Pt,Ir, Au, W) (PERSS®) as described in US-2003-0018380-A1,US-2002-0144757-A1, and US-2003-0077200-A1), Nitinol (a nickel-titaniumalloy), cobalt alloys such as Elgiloy, L605 alloys, MP35N, titanium,titanium alloys (e.g., Ti-6Al-4V, Ti-50Ta, Ti-10Ir), platinum, platinumalloys, niobium, niobium alloys (e.g., Nb-1Zr) Co-28Cr-6Mo, tantalum,and tantalum alloys. Other examples of materials are described incommonly assigned U.S. application Ser. No. 10/672,891, filed Sep. 26,2003; and U.S. application Ser. No. 11/035,316, filed Jan. 3, 2005. Thestent can be formed of bioerodible metal such as magnesium, iron,calcium, aluminum, or their alloys. Other materials include elasticbiocompatible metal such as a superelastic or pseudo-elastic metalalloy, as described, for example, in Schetsky, L. McDonald, “ShapeMemory Alloys”, Encyclopedia of Chemical Technology (3rd ed.), JohnWiley & Sons, 1982, vol. 20. pp. 726-736; and commonly assigned U.S.application Ser. No. 10/346,487, filed Jan. 17, 2003.

The stents described herein can be configured for vascular, e.g.coronary and peripheral vasculature or non-vascular lumens. For example,they can be configured for use in the esophagus or the prostate. Otherlumens include biliary lumens, hepatic lumens, pancreatic lumens, andurethral lumens.

The stent can be of a desired shape and size (e.g., coronary stents,aortic stents, peripheral vascular stents, gastrointestinal stents,urology stents, tracheal/bronchial stents, and neurology stents).Depending on the application, the stent can have a diameter of between,e.g., about 1 mm to about 46 mm. In certain embodiments, a coronarystent can have an expanded diameter of from about 2 mm to about 6 mm. Insome embodiments, a peripheral stent can have an expanded diameter offrom about 4 mm to about 24 mm. In certain embodiments, agastrointestinal and/or urology stent can have an expanded diameter offrom about 6 mm to about 30 mm. In some embodiments, a neurology stentcan have an expanded diameter of from about 1 mm to about 12 mm. Anabdominal aortic aneurysm (AAA) stent and a thoracic aortic aneurysm(TAA) stent can have a diameter from about 20 mm to about 46 mm. Thestent can be balloon-expandable, self-expandable, or a combination ofboth (e.g., U.S. Pat. No. 6,290,721). Other medical devices,particularly implantable devices can be formed, such as catheters, guidewires, and filters, having implants and electrodes.

A number of embodiments have been described in the disclosure.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the disclosure. Forexample, referring back to FIG. 3, the first coating 25, e.g., apolymeric coating can be provided as well or only on the adluminalsurface and/or cut-face surfaces; while the second coating, e.g., aporous ceramic coating, can be provided only on the abluminal surface oras well on the cut-face surfaces. Also for another example, a stentformed of a polymeric material (e.g., a biostable polymer such aspolyurethane or a bioerodible polymer such as poly(lactic-co-glycolicacid)) can be coated with a similar construction on select surfaces asdiscussed above, e.g., a DEP or drug coating covered with a porousceramic or metallic layer over the abluminal surface. In a particularexample, in case of a bioerodible polymer stent, porous iron ormagnesium can be the over coating. The bioerodible stent can also becovered with an initial porous ceramic or metallic underlayer (e.g., abioerodible ceramic or metal, for example, calcium carbonate or iron),after which a DEP can be applied to select regions of the underlayer,which then is covered with a porous ceramic or metal over coating. Suchan arrangement allows that the drug eluting process lasts longer thenthe stent erosion process: the drug elutes only through the over coatingif the stent is still intact and the drug can elute both through theover coating and the underlayer once the stent is eroded.

All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference herein in their entirety.

Still other embodiments are in the following claims.

1. An endoprosthesis, comprising: a first coating comprising a polymer,and a second coating over the first coating formed of a porous ceramic,wherein the porous ceramic has a smooth globular morphology to enhanceendothelial cell growing over the second coating, the globularmorphology having a series of shallow globular features and the globularfeatures having a local maxima width of about 100 nm or less and a peakheight of about 50 nm or less.
 2. The endoprosthesis of claim 1, whereinthe polymer includes a drug.
 3. The endoprosthesis of claim 1, whereinthe ceramic iridium oxide, titanium oxide, tantalum oxide, or niobiumoxide.
 4. The endoprosthesis of claim 1, wherein the first coating has aplurality of depressions.
 5. The endoprosthesis of claim 1, wherein thesecond coating has pores with a pore diameter of about 1 nm to about 20nm.
 6. The endoprosthesis of claim 1, wherein the thickness of thesecond coating is about 10 to about 500 nm.
 7. The endoprosthesis ofclaim 1, wherein the thickness of the first coating is about 0.1 toabout 10 micron.
 8. The endoprosthesis of claim 1, wherein the firstcoating contacts a surface of an endoprosthesis body.
 9. Theendoprosthesis of claim 8, wherein the endoprosthesis body is formed ofa metal.
 10. The endoprosthesis of claim 8, wherein the endoprosthesisbody is formed of a polymer.
 11. The endoprosthesis of claim 10, whereinthe polymer is a bioerodible polymer.
 12. The endoprosthesis of claim10, wherein the polymer is a biostable polymer.
 13. The endoprosthesisof claim 1, further comprising a third coating under the first coating,the third coating formed of a ceramic having a high roughness definedgrain morphology.
 14. The endoprosthesis of claim 1, wherein theglobular morphology has a developed interfacial area ratio of between 8and
 15. 15. A method of forming an endoprosthesis, comprising: forming apolymer coating on the endoprosthesis wherein the polymer coatingcomprises a drug, and forming a layer of porous ceramic or metal overthe drug-containing polymer coating, wherein the porous ceramic has asmooth globular morphology to enhance endothelial cell growing over theporous ceramic, the globular morphology having a series of shallowglobular features and the globular features having a local maxima widthof about 100 nm or less and a peak height of about 50 nm or less. 16.The method of claim 15, comprising forming the polymer coating byspraying a solution of a polymer and a drug to a surface of anendoprosthesis body.
 17. The method of claim 15, comprising introducingthe drug by coating, dipping, or spraying.
 18. The method of claim 15,comprising forming the polymer coating by introducing a polymer bydipping, spraying, brushing, pressing, laminating, or pulsed laserdeposition.
 19. The method of claim 15 comprising introducing the drugby pulsed laser deposition.
 20. The method of claim 15 comprisingforming the porous ceramic layer by pulsed laser deposition.
 21. Themethod of claim 15, further comprising forming depressions in thepolymer coating by laser irradiation.
 22. An endoprosthesis, comprising:a first coating comprising a polymer; a second coating over the firstcoating, the second coating being formed of a porous ceramic having asmooth globular morphology, the globular morphology having a series ofshallow globular features and the globular features having a localmaxima width of about 100 nm or less and a peak height of about 50 nm orless, and a third coating under the first coating, the third coatingbeing formed of a ceramic having a high roughness defined grainmorphology.